A Self-Reinforcing Nanozyme Platform for Synergistic Ferroptosis–Apoptosis Therapy via Amplified Reactive Oxygen Species Generation and Calcium Overload

In recent years, pro-apoptotic therapy has attracted significant attention. However, single-mode treatment is often less effective due to the tumor’s ability to evade apoptosis. Ferroptosis, a nonapoptotic cell death pathway, has emerged as a promising strategy to overcome apoptosis resistance and enhance treatment efficacy. Therefore, developing materials capable of coinducing apoptosis and ferroptosis is critically needed. Nanozymes have demonstrated significant potential for inducing ferroptosis, owing to their capability to catalyze reactive oxygen species (ROS) production within the tumor microenvironment (TME). Nevertheless, their effectiveness is often limited by poor affinity and inadequate levels of H₂O₂and O₂in the TME. To address these challenges, we encapsulated Pd nanocubes within CaO₂nanoparticles to develop a self-reinforcing nanozyme platform, Pd@CaO₂NPs (PC NPs), for synergistic ferroptosis–apoptosis therapy. Upon exposure to the acidic TME, CaO₂decomposes, releasing H₂O₂, O₂, and Ca²⁺. This simultaneously alleviates tumor hypoxia and supplies substrates necessary for catalytic ROS generation. PC NPs exhibit dual peroxidase- and oxidase-like activities, efficiently converting H₂O₂into hydroxyl radicals (•OH) and O₂into superoxide anions (O₂^•–), thereby amplifying intracellular ROS levels. This surge in ROS depletes glutathione, suppresses GPX4 expression, and promotes lipid peroxidation, ultimately triggering ferroptosis. Simultaneously, the exogenously released Ca²⁺mediates Ca²⁺overload, leading to mitochondrial dysfunction and subsequent apoptosis. Importantly, the increase in ROS facilitates calcium accumulation, while mitochondrial damage further increases ROS production. This establishes a self-reinforcing feedback loop that amplifies both ferroptosis and apoptosis pathways. In vitro and in vivo studies confirm the potent tumor-suppressive effects of PC NPs. This study introduces a nanozyme platform capable of simultaneously inducing apoptosis and ferroptosis, and its self-enhancing property represents a promising therapeutic approach for tumors.